Dosing regimen

ABSTRACT

This invention relates to a method of treatment and dosing regimen for treating mammalian tumors by the discontinuous administration of a farnesyl transferase inhibitor over an abbreviated one to five day dosing schedule.

FIELD OF THE INVENTION

[0001] The present invention relates to a method for treating mammaliantumors by the administration of a farnesyl protein transferase (FPT)inhibitor using an intermittent dosing schedule. The regimen involvesthe administration of a FPT inhibitor over an abbreviated one to fiveday dosing schedule whereby anticancer effects are achieved whichcontinue beyond the period of administration.

BACKGROUND OF THE INVENTION

[0002] Over the last decade cancer research has identified specificgenetic lesions which induce malignant transformation and drive tumorgrowth. It is now recognized that mutations, deletions or alterations inthe expression of normal mammalian genes involved in growth controlconverts these “protooncogenes” into “oncogenes”. The ras family ofoncogenes consisting of H-ras, K-ras and N-ras oncogenes encode a highlyconserved GTP-binding protein or Mr=21,000 (p21).

[0003] Oncogenes frequently encode components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellullar transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. In order toacquire transforming potential the precursor of the ras oncoprotein mustundergo farnesylation of the cysteine residue located in acarboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzesthis modification, farnesyl protein tranferase, have therefore beensuggested as anticancer agents for tumors in which ras contributes totransformation. Mutated oncogenic forms of ras are frequently found inmany human cancers, most notably in more than 50% of colon andpancreatic carcinomas (Kohl et al., Science, vol. 260, 1384 to 1837,1993).

[0004] The protein products of the ras ocogenes have been the focus ofoncology drug discovery efforts because of some unique features of thecellular metabolism of these proteins. To function in signaltransduction and cell transformation, ras must attach to the plasmamembrane to promote interactions with membrane localization also SH2/SH3domain adaptor proteins Grb2 and SOS. Ras membrane localization alsofunctions in the activation of downstream effectors such as Raf proteinkinase. Newly synthesized Ras proteins must pe posttranslationallymodified in mammalian cells by farnesylation followed by theproteolytiac cleavage of the three terminal amino acids andcarboxy-O-methylation to produce the hydrophobicity or recognition siteswhich allow proper membrane localization. The initial and rate-limitingpost-translational modification of Ras involves the covalent attachmentof farnesol via a thioether linkage to a single cysteine residuepositioned four amino acids from the carboxy terminus of the protein.This reaction is catalyzed by farnesyl protein transferase (FPT). Theenzyme requires only the four C-terminal amino acids or CAAX motif forspecific binding and catalysis of protein substrates.

[0005] Farnesyl protein transferase inhibitors have been described asbeing useful in the treatment of mammalian cancers and in particular inthe treatment of colon and pancreatic cancers.

[0006] WO-97/21701 describes the preparation, formulation andpharmaceutical properties of farnesyl protein transferase inhibiting(imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II)and (III), as well as intermediates of formula (II) and (III) that aremetabolized in vivo to the compounds of formula (I). The compounds offormulas (I), (II) and (III) are represented by

[0007] the pharmaceutically acceptable acid or base addition salts andthe stereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond;

[0008] X is oxygen or sulfur;

[0009] R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,quinolinylC₁₋₆alkyl, pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)-R⁹ or—Alk¹—S(O)₂—R⁹,

[0010] wherein Alk¹ is C₁₋₆alkanediyl, R⁹ is hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl;

[0011] R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo,cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyl-oxy, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or when on adjacentpositions R² and R³ taken together may form a bivalent radical offormula

—O—CH₂—O—  (a-1)

—O—CH₂—CH₂—O—  (a-2)

—O—CH═CH—  (a-3)

—O—CH₂—CH₂—  (a-4)

—O—CH₂—CH₂—CH₂—  (a-5)

[0012] or

—CH═CH—CH═CH—  (a-6)

[0013] R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0014] R⁶ and R⁷ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C ₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio,di(C₁₋₆alkyl)amino, or when on adjacent positions R⁶ and R⁷ takentogether may form a bivalent radical of formula

—O—CH₂—O—  (c-1)

[0015] or

—CH═CH—CH═CH—  (c-2)

[0016] R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula

—O—R¹⁰  (b-1)

—S—R¹⁰  (b-2)

—N—R¹¹R¹²  (b-3)

[0017] wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl-C₁₋₆alkyl, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

[0018] R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;

[0019] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkylcarbonyl-C₁₋₆alkyl, a natural amino acid, Ar¹carbonyl,Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkyl amino,C₁₋₆alkylcarbonylamino, or a radical or formula -Alk²—OR¹³ or—Alk²—NR¹⁴R¹⁵;

[0020] wherein Alk² is C₁₋₆alkanediyl;

[0021] R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy-C₁₋₆alkyl,Ar¹ or Ar²C₁₋₆alkyl;

[0022] R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;

[0023] R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ orAr²C₁₋₆alkyl;

[0024] R¹⁷ is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,Ar¹;

[0025] R¹⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

[0026] R¹⁹ is hydrogen or C₁₋₆alkyl;

[0027] Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo; and

[0028] Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo.

[0029] WO-97/16443 concerns the preparation, formulation andpharmaceutical properties of farnesyl protein transferase inhibitingcompounds of formula (IV), as well as intermediates of formula (V) and(VI) that are metabolized in vivo to the compounds of formula (IV). Thecompounds of formulas (IV), (V) and (VI) are represented by

[0030] the pharmaceutically acceptable acid or base addition salts andthe stereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond;

[0031] X is oxygen or sulfur;

[0032] R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula -—Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹or —Alk¹—S(O)₂—R⁹,

[0033] wherein Alk¹ is C₁₋₆alkanediyl, R⁹ is hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl;

[0034] R² and R³ each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,amino-C₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar²C₁₋₆alkyl, Ar²oxy, Ar²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl; or

[0035] when on adjacent positions R² and R³ taken together may form abivalent radical of formula

—O—CH₂—O—  (a-1)

—O—CH₂—CH₂—O—  (a-2)

—O—CH═CH—  (a-3)

—O—CH₂—CH₂—  (a-4)

—O—CH₂—CH₂—CH₂—  (a-5)

[0036] or

—CH═CH—CH═CH—  (a-6)

[0037] R⁴ and R⁵ each independently are hydrogen, Art, C₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0038] R⁶ and R⁷ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy or Ar²oxy;

[0039] R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl-carbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, hydroxy-carbonylC₁₋₆alkyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, Ar¹,Ar²C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl;

[0040] R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

[0041] R¹¹ is hydrogen or C₁₋₆alkyl;

[0042] Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo;

[0043] Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo.

[0044] WO-98/40383 concerns the preparation, formulation andpharmaceutical properties of farnesyl protein transferase inhibitingcompounds of formula (VII)

[0045] the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

[0046] the dotted line represents an optional bond;

[0047] X is oxygen or sulfur;

[0048] —A— is a bivalent radical of formula —CH═CH— (a-1), —CH₂—S—(a-6), —CH₂—CH₂— (a-2), —CH₂—CH₂—S— (a-7), —CH₂—CH₂—CH₂— (a-3), —CH═N—(a-8), —CH₂—O— (a-4), —N═N— (a-9), or —CH₂—CH₂—O— (a-5), —CO—NH— (a-10);

[0049] wherein optionally one hydrogen atom may be replaced by C₁₋₄alkylor Ar¹;

[0050] R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar²,Ar²-C₁₋₆alkyl, Ar²-oxy, Ar²—C₁₋₆alkyloxy; or when on adjacent positionsR¹ and R² taken together may form a bivalent radical of formula

—O—CH₂—O—  (b-1)

—O—CH₂—CH₂—O—  (b-2)

—O—CH═CH—  (b-3)

—O—CH₂—CH₂—  (b-4)

—O—CH₂—CH₂—CH₂—  (b-5)

[0051] or

—CH═CH—CH═CH—  (b-6)

[0052] R³ and R⁴ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, Ar³-oxy, C₋₆alkylthio, di(C₁₋₆alkyl) amino,trihalomethyl, trihalomethoxy, or when on adjacent positions R³ and R⁴taken together may form a bivalent radical of formula

—O—CH₂—O—  (c-1)

—O—CH₂—CH₂—O—  (c-2)

[0053] or

—CH═CH—CH═CH—  (c-3)

[0054] R⁵ is a radical of formula

[0055] wherein R¹³ is hydrogen, halo, Ar⁴, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxy-C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxy-carbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0056] R¹⁴is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

[0057] R⁶ is hydrogen, hydroxy, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar⁵,Ar⁵—C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula

—O—R⁷  (e-1)

—S—R⁷  (e-2)

—N—R⁸R⁹  (e-3)

[0058] wherein R⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar⁶,Ar⁶—C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—Alk—OR¹⁰ or —Alk—NR¹¹R¹²;

[0059] R⁸ is hydrogen, C₁₋₆alkyl, Ar⁷ or Ar⁷—C₁₋₆alkyl;

[0060] R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar⁸, Ar⁸—C₁₋₆alkyl,C₁₋₆alkylcarbonyl-C₁₋₆alkyl, Ar⁸-carbonyl, Ar⁸-C₁₋₆alkylcarbonyl,aminocarbonyl-carbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula-Alk—OR¹⁰ or —Alk—NR¹¹R¹²;

[0061] wherein Alk is C₁₋₆alkanediyl;

[0062] R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy-C₁₋₆alkyl,Ar⁹ or Ar⁹—C₁₋₆alkyl;

[0063] R¹¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹⁰ orAr¹⁰—C₁₋₆alkyl;

[0064] R ¹² is hydrogen, C₁₋₆alkyl, Ar¹¹ or Ar¹¹—C₁₋₆alkyl; and

[0065] Ar¹ to Ar¹¹ are each independently selected from phenyl; orphenyl substituted with halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl.

[0066] WO-98/49157 concerns the preparation, formulation andpharmaceutical properties of farnesyl protein transferase inhibitingcompounds of formula (VIII)

[0067] the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond;

[0068] X is oxygen or sulfur;

[0069] R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar¹C₁₋₆alkyl, Ar¹oxy or Ar¹C₁₋₆alkyloxy;

[0070] R³ and R⁴ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, Ar¹oxy, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,trihalomethyl or trihalomethoxy;

[0071] R⁵ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar¹,Ar¹C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula

—O—R¹⁰  (a-1)

—S—R¹⁰  (a-2)

—N—R¹¹R¹²  (a-3)

[0072] wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar¹C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;

[0073] R¹¹ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;

[0074] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar¹C₁₋₆alkyl,C₁₋₆alkylcarbonyl-C₁₋₆alkyl, Ar¹carbonyl, Ar¹C₁₋₆alkylcarbonyl,aminocarbonyl-carbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula—Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;

[0075] wherein Alk is C₁₋₆alkanediyl;

[0076] R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy-C₁₋₆alkyl,Ar¹ or Ar¹C₁₋₆alkyl;

[0077] R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;

[0078] R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ orAr¹C₁₋₆alkyl;

[0079] R⁶ is a radical of formula

[0080] wherein R¹⁶is hydrogen, halo, Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxy-C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0081] R¹⁷is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

[0082] R⁷ is hydrogen or C₁₋₆alkyl provided that the dotted line doesnot represent a bond;

[0083] R⁸ is hydrogen, C₁₋₆alkyl or Ar²CH₂ or Het¹CH₂;

[0084] R⁹ is hydrogen, C₁₋₆alkyl , C₁₋₆alkyloxy or halo; or

[0085] R⁸ and R⁹ taken together to form a bivalent radical of formula

—CH═CH—  (c-1)

—CH₂—CH₂—  (c-2)

—CH₂—CH₂—CH₂—  (c-3)

—CH₂—O—  (c-4)

[0086] or

—CH₂—CH₂—O—  (c-5)

[0087] Ar¹ is phenyl; or phenyl substituted with 1 or 2 substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl;

[0088] Ar² is phenyl; or phenyl substituted with 1 or 2 substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl; and

[0089] Het¹ is pyridinyl; pyridinyl substituted with 1 or 2 substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl.

[0090] WO-00/39082 concerns the preparation, formulation andpharmaceutical properties of farnesyl protein transferase inhibitingcompounds of formula (IX)

[0091] or the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein ═X¹—X²—X³— is atrivalent radical of formula ═N—CR⁶═CR⁷— (x-1), ═CR⁶—CR⁷═CR⁸— (x-6),═N—N═CR⁶— (x-2), ═CR⁶—N═CR⁷— (x-7), ═N—NH—C(═O)— (x-3), ═CR⁶—NH—C(═O)—(x-8), or ═N—N═N— (x-4), ═CR⁶—N═N— (x-9); ═N—CR⁶═N— (x-5),

[0092] wherein each R⁶, R⁷ and R⁸ are independently hydrogen, C₁₋₄alkyl,hydroxy, C₁₋₄alkyloxy, aryloxy, C₁₋₄alkyloxycarbonyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl, cyano,amino, thio, C₁₋₄alkylthio, arylthio or aryl;

[0093] >Y¹-Y² is a trivalent radical of formula

>CH—CHR⁹—  (y-1)

>C═N—  (y-2)

>CH—NR⁹—  (y-3)

[0094] or

>C═CR⁹—  (y-4)

[0095] wherein each R⁹ independently is hydrogen, halo, halocarbonyl,aminocarbonyl, hydroxyC₁₋₄alkyl, cyano, carboxyl, C₁₋₄alkyl,C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, mono- ordi(C₁₋₄alkyl)amino, mono- or di(C¹⁻⁴alkyl)aminoC₁₋₄alkyl, aryl;

[0096] r and s are each independently 0, 1, 2, 3, 4 or 5;

[0097] t is 0, 1, 2 or 3;

[0098] each R¹ and R² are independently hydroxy, halo, cyano, C₁₋₆alkyl,trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)amino,mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, aryloxy orarylC₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminocarbonyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl; or

[0099] two R¹ or R² substituents adjacent to one another on the phenylring may independently form together a bivalent radical of formula

—O—CH₂—O—  (a-1)

—O—CH₂—CH₂—O—  (a-2)

—O═CH═CH—  (a-3)

—O—CH₂—CH₂—  (a-4)

—O—CH₂—CH₂—CH₂—  (a-5)

[0100] or

—CH═CH—CH═CH—  (a-6)

[0101] R³ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, hydroxycarbonyl,hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, C ₁₋₆alkyloxycarbonyl, aryl,arylC₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl; or aradical of formula

—O—R¹⁰  (b-1)

—S—R¹⁰  (b-2)

—NR¹¹R¹²  (b-3)

[0102] wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl,arylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;

[0103] R¹¹ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;

[0104] R¹² is hydrogen, C₁₋₆alkyl, aryl, hydroxy, amino, C₁₋₆alkyloxy,C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl, C₁₋₆alkylcarbonylamino, mono-or di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonyl, aminocarbonyl, arylcarbonyl,haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonylwherein the alkyl moiety may optionally be substituted by one or moresubstituents independently selected from aryl or C₁₋₃alkyloxycarbonyl,aminocarbonylcarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, ora radical or formula —Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;

[0105] wherein Alk is C₁₋₆alkanediyl;

[0106] R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl,aryl or arylC₁₋₆alkyl;

[0107] R¹⁴ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;

[0108] R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl orarylC₁₋₆alkyl;

[0109] R⁴ is a radical of formula

[0110] wherein R¹⁶ is hydrogen, halo, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆aikyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino, mono- ordi(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0111] R¹⁶ may also be bound to one of the nitrogen atoms in theimidazole ring of formula (c-1) or (c-2), in which case the meaning ofR¹⁶ when bound to the nitrogen is limited to hydrogen, aryl, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0112] R¹⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyl,trifluoromethyl or di(C₁₋₄alkyl)aminosulfonyl;

[0113] R⁵ is C₁₋₆alkyl , C₁₋₆alkyloxy or halo; aryl is phenyl,naphthalenyl or phenyl substituted with 1 or more substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl.

[0114] Other useful farnesyl protein transferase inhibitors includeArglabin (i.e.1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olidedescibed in WO-98/28303 (NuOncology Labs); perrilyl alcohol described inWO-99/45912 (Wisconsin Genetics); SCH-66336, i.e.(+)-(R)-4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide,described in U.S. Pat. No. 5874442 (Schering); L778123, i.e.1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,described in WO-00/01691 (Merck); compound2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone described in WO-94/10138 (Merck); and BMS 214662, i.e.(R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile,described in WO 97/30992 (Bristol Myers Squibb) and Pfizer compounds (A)and (B) described in WO-00/12498 and WO-00/12499:

[0115] The compounds are generally described as being inhibitors offarnesyl protein transferase useful in the treatment of mammaliantumors. Generally in the treatment of cancerous tumors about 0.01mg/kgto 100mg/kg body weight of a farnesyl protein transferase inhibitor isadministered at doses of about two, three, four or more sub doses atappropriate intervals throughout the day. This dosing schedule ispredicated on the hypothesis that continuous exposure to the activecompound and resultant inhibition of FPT were required in order tomaintain antitumor effects.

[0116] Unexpectedly, it has been found that an interrupted dosingregimen of about five days containing a farnesyl protein transferaseinhibitor as the active ingredient followed by about two weeks withouttreatment results in suppression of mammalian tumor growth.

[0117] It is an object of the present invention to provide a method oftreatment and a dosing regimen comprising a discontinuous dosingschedule in which a farnesyl protein transferase inhibitor isadministered to suppress mammalian tumor growth. The regimen comprisesthe administration of a single dose of a farnesyl protein transferaseinhibitor over a one to five day period followed by at least two weekswithout treatment.

SUMMARY OF THE INVENTION

[0118] The present invention relates to a method of treating mammaliantumors which comprises administering a single dose of a farnesyl proteintransferase inhibitor over a one to five day period. The invention alsorelates to an antitumor dosage regimen in which suppression of tumorgrowth is achieved by the administration of a farnesyl proteintransferase inhibitor over a one to five day period followed by at leasttwo weeks without treatment. The transient one to five day exposure ofmammalian tumors to a farnesyl protein transferase inhibitor producessustained antitumor effects. The inhibition of FPT by a FPT inhibitorunder the method and regimen of the present invention produces lastingalterations in the malignant process which recover only very slowly.

DETAILED DESCRIPTION OF THE INVENTION

[0119] Inhibitors of farnesyl transferase (FPT) are known to be usefulin the treatment of mammalian tumors and in particular colon andpancreatic carcinomas. In previous studies farnesyl protein transferaseinhibitors have been shown to inhibit the growth of mammalian tumorswhen administered as a twice daily dosing schedule. It has beenunexpectedly been found that administration of a farnesyl proteintransferase inhibitor in a single dose daily for one to five daysproduced a marked suppression of tumor growth lasting out to at least 21days. In particular, administration of a farnesyl protein transferaseinhibitor at a single dose between 50-1200 mg/kg body weight once dailyfor one to five consecutive days after tumor formation produces a markedsuppression of tumor growth lasting out to 21 or more days. The effectis equivalent to administering a farnesyl protein transferase inhibitorcontinuously at a daily 50mg/kg-100 mg/kg dose in the same tumor model.Upon the appearance of growth in tumors treated according to the methodand/or regimen of this invention, rechallenge with the FPT inhibitor atday 21 produced growth arrest indicating that tumor growth did notemerge from resistant tumor cells. Suppression of tumor growth wasdose-related at doses from 50-1200 mg/kg body weight with the five daysingle dosing schedule. The preferred dosage range is 50-400 mg/kg with200 mg/kg being the most preferred dose. In man based on early Phase 1data, the preferred dose range of 200 to 2400 mg can be expected. Thefinding that a persistent suppression of tumor growth can be obtainedwith only one to five days of treatment with a farnesyl proteintransferase inhibitor was unexpected since it has been assumed thatfarnesyl protein transferase inhibitors as a class would require chroniccontinuous exposure in order to maintain uninterrupted inhibition ofprotein farnesylation. Examples of FTI inhibitors which may be employedin accordance with the present invention include compounds of formula(I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) above, moreparticularly compounds of formula (I), (II) or (III):

[0120] the pharmaceutically acceptable acid or base addition salts andthe stereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond;

[0121] X is oxygen or sulfur;

[0122] R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or—Alk¹—S(O)₂—R⁹,

[0123] wherein Alk¹ is C₁₋₆alkanediyl,

[0124] R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or

[0125] C₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;

[0126] R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo,cyano, C₁₋₆alky, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or

[0127] when on adjacent positions R² and R³ taken together may form abivalent radical of formula

—O—CH₂—O—  (a-1)

—O—CH₂—CH₂—O—  (a-2)

—O—CH═CH—  (a-3)

—O—CH₂—CH₂—  (a-4)

—O—CH₂—CH₂—CH₂—  (a-5)

[0128] or

—CH═CH—CH═CH—  (a-6)

[0129] R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0130] R⁶ and R⁷ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio,di(C₁₋₆alkyl)amino, or when on adjacent positions R⁶ and R⁷ takentogether may form a bivalent radical of formula

—O—CH₂—O—  (c-1

[0131] or

—CH═CH—CH═CH—  (c-2)

[0132] R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula

—O—R¹⁰  (b-1)

—S—R¹⁰  (b-2)

—N—R¹¹R¹²  (b-3)

[0133] wherein R¹⁰is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical or formula—Alk²—OR¹³ or —Alk²-NR¹⁴R¹⁵;

[0134] R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;

[0135] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkylcarbonyl-C₁₋₆alkyl, a natural amino acid, Ar¹carbonyl,Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula —Alk²—OR¹³ or—Alk²—NR¹⁴R¹⁵;

[0136] wherein Alk² is C₁₋₆alkanediyl;

[0137] R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy-C₁₋₆alkyl,Ar¹ or Ar²C₁₋₆alkyl;

[0138] R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;

[0139] R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ orAr²C₁₋₆alkyl;

[0140] R¹⁷is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,Ar¹;

[0141] R¹⁸is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

[0142] R¹⁹ is hydrogen or C₁₋₆alkyl;

[0143] Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo; and

[0144] Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo.

[0145] In Formulas (I), (II) and (III), R⁴ or R⁵ may also be bound toone of the nitrogen atoms in the imidazole ring. In that case thehydrogen on the nitrogen is replaced by R⁴ or R⁵ and the meaning of R⁴and R⁵ when bound to the nitrogen is limited to hydrogen, Ar¹,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl, C₁₋₆alkylS(O)₂C₁₋₆alkyl.

[0146] Preferably the substituent R¹⁸ is situated on the 5 or 7 positionof the quinolinone moiety and substituent R¹⁹ is situated on the 8position when R¹⁸ is on the 7-position.

[0147] Interesting compounds are these compounds of formula (I) whereinX is oxygen.

[0148] Also interesting compounds are these compounds of formula (I)wherein the dotted line represents a bond, so as to form a double bond.

[0149] Another group of interesting compounds are those compounds offormula (I) wherein R¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹,wherein Alk¹ is methylene and R⁹ is C₁₋₈alkyl-amino substituted withC₁₋₆alkyloxycarbonyl.

[0150] Still another group of interesting compounds are those compoundsof formula (I) wherein R³ is hydrogen or halo; and R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy orhydroxyC₁₋₆alkyloxy.

[0151] A further group of interesting compounds are those compounds offormula (I) wherein R² and R³ are on adjacent positions and takentogether to form a bivalent radical of formula (a-1), (a-2) or (a-3).

[0152] A still further group of interesting compounds are thosecompounds of formula (I) wherein R⁵ is hydrogen and R⁴ is hydrogen orC₁₋₆alkyl.

[0153] Yet another group of interesting compounds are those compounds offormula (I) wherein R⁷ is hydrogen; and R⁶ is C₁₋₆alkyl or halo,preferably chloro, especially 4-chloro.

[0154] A particular group of compounds are those compounds of formula(I) wherein R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxy-carbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is hydrogen or C₁₋₆alkyl.

[0155] Preferred compounds are those compounds wherein R¹ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or aradical of formula —Alk^(1—-C(═O)—R) ⁹, wherein Alk¹ is methylene and R⁹is C₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl; R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy,hydroxyC₁₋₆alkyloxy or Ar¹; R³ is hydrogen; R⁴ is methyl bound to thenitrogen in 3-position of the imidazole; R⁵ is hydrogen; R⁶ is chloro;R⁷ is hydrogen; R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,imidazolyl, or a radical of formula —NR¹¹R¹² wherein R¹¹ is hydrogen orC₁₋₁₂alkyl and R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is C₁₋₆alkyl; R¹⁷ is hydrogen and R¹⁸ is hydrogen.

[0156] Most preferred compounds are

[0157]4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

[0158]6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;

[0159]6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride.monohydrate;

[0160]6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone;a stereoisomeric form thereof or a pharmaceutically acceptable acid orbase addition salt; and

[0161](+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(Compound 75 in Table 1 of the Experimental part of WO-97/21701) ; or apharmaceutically acceptable acid addition salt thereof. The lattercompound is especially preferred.

[0162] Further preferred embodiments of the present invention includecompounds of formula (IX) wherein one or more of the followingrestrictions apply:

[0163] ═X¹—X²—X³ is a trivalent radical of formula (x-1), (x-2), (x-3),(x-4) or (x-9) wherein each R⁶ independently is hydrogen, C₁₋₄alkyl,C₁₋₄alkyloxycarbonyl, amino or aryl and R⁷ is hydrogen;

[0164] >y1-y2- is a trivalent radical of formula (y-1), (y-2), (y-3), or(y-4) wherein each R⁹ independently is hydrogen, halo, carboxyl,C₁₋₄alkyl or C₁₋₄alkyloxycarbonyl;

[0165] r is 0, 1 or 2;

[0166] s is 0 or 1;

[0167] t is 0;

[0168] R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one anotheron the phenyl ring may independently form together a bivalent radical offormula (a-1);

[0169] R² is halo;

[0170] R³ is halo or a radical of formula (b-1) or (b-3) wherein

[0171] R¹⁰ is hydrogen or a radical of formula —Alk—OR¹³.

[0172] R¹¹ is hydrogen;

[0173] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;

[0174] Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;

[0175] R⁴ is a radical of formula (c-1) or (c-2) wherein

[0176] R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino;

[0177] R¹⁷ is hydrogen or C₁₋₆alkyl;

[0178] aryl is phenyl.

[0179] A particular group of compounds consists of those compounds offormula (IX) wherein ═2 X¹-X²-X³ is a trivalent radical of formula(x-1), (x-2), (x-3), (x-4) or (x-9), >Y1-Y2 is a trivalent radical offormula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R¹ is halo,C₁₋₄)alkyl or forms a bivalent radical of formula (a-1), R² is halo orC₁₋₄alkyl, R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁴ isa radical of formula (c-1) or (c-2), R⁶ is hydrogen, C₁₋₄alkyl orphenyl, R⁷ is hydrogen, R⁹ is hydrogen or C₁₋₄alkyl, R¹⁰ is hydrogen or—Alk—OR¹³, R¹¹ is hydrogen and R¹² is hydrogen or C₁₋₆alkylcarbonyl andR¹³ is hydrogen;

[0180] Preferred compounds are those compounds of formula (IX) wherein═X¹-X²-X³ is a trivalent radical of formula (x-1) or (x-4), >Y1-Y2 is atrivalent radical of formula (y-4), r is 0 or 1, s is 1, t is 0, R¹ ishalo, preferably chloro and most preferably 3-chloro, R² is halo,preferably 4-chloro or 4-fluoro, R³ is hydrogen or a radical of formula(b-1) or (b-3), R⁴ is a radical of formula (c-1) or (c-2), R⁶ ishydrogen, R⁷ is hydrogen, R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ ishydrogen and R¹² is hydrogen;

[0181] Other preferred compounds are those compounds of formula (IX)wherein -X¹-X²-X³ is a trivalent radical of formula (x-2), (x-3) or(x-4), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), rand s are 1, t is 0, R¹ is halo, preferably chloro, and most preferably3-chloro or R¹ is C₁₋₄alkyl, preferably 3-methyl, R² is halo, preferablychloro, and most preferably 4-chloro, R³ is a radical of formula (b-1)or (b-3), R⁴ is a radical of formula (c-2), R⁶ is C₁₄alkyl, R⁹ ishydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen or hydroxy.

[0182] The most preferred compounds of formula (IX) are

[0183]7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline;α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo,[1,2-a]quinoline-7-methanol;

[0184] 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-imidazo[1,2-a-]quinoline-7-methanol;

[0185]5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a-]quinoline-7-methanamine;

[0186]5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;

[0187]5-(3-chlorophenyl)-α-(4-chlorophenyl)-1-methyl-α-1-methyl-1H-imidazol-5-yl)-1,2,4-triazolo[4,3-a]quinoline-7-methanol;

[0188]5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;

[0189]5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;

[0190]5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;

[0191]5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine;

[0192]5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine;

[0193]α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[1,5-a]quinoline-7-methanamine; the pharmaceutically acceptable acidaddition salts and the stereochemically isomeric forms thereof.

[0194]5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine,especially the (-) enantiomer, and its pharmaceutically acceptable acidaddition salts are especially preferred.

[0195] As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₆alkyl defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl andthe like; C₁₋₈alkyl encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₁₋₆alkyl as well as thehigher homologues thereof containing 7 or 8 carbon atoms such as, forexample heptyl or octyl; C₁₋₁₂alkyl again encompasses C₁₋₈alkyl and thehigher homologues thereof containing 9 to 12 carbon atoms, such as, forexample, nonyl, decyl, undecyl, dodecyl; C₁₋₁₆alkyl again encompassesC₁₋₁₂alkyl and the higher homologues thereof containing 13 to 16 carbonatoms, such as, for example, tridecyl, tetradecyl, pentedecyl andhexadecyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals containing one double bond and having from 2 to 6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, and the like; C₁₋₆alkanediyl definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refersto a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to asulfon. The term “natural amino acid” refers to a natural amino acidthat is bound via a covalent amide linkage formed by loss of a moleculeof water between the carboxyl group of the amino acid and the aminogroup of the remainder of the molecule. Examples of natural amino acidsare glycine, alanine, valine, leucine, isoleucine, methionine, proline,phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine.

[0196] The pharmaceutically acceptable acid or base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and non-toxic base addition salt forms which thecompounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII)or (IX) are able to form. The compounds of formulas (I), (II), (III),(IV), (V), (VI), (VII), (VIII) or (IX) which have basic properties canbe converted in their pharmaceutically acceptable acid addition salts bytreating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

[0197] The compounds of formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII) or (IX) which have acidic properties may be converted intheir pharmaceutically acceptable base addition salts by treating saidacid form with a suitable organic or inorganic base.

[0198] Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabaminesalts, and salts with amino acids such as, for example, arginine, lysineand the like.

[0199] The terms acid or base addition salt also comprise the hydratesand the solvent addition forms which the compounds of formulae (I),(II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

[0200] The term stereochemically isomeric forms of compounds of formulae(I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), as usedhereinbefore, defines all possible compounds made up of the same atomsbonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII)or (IX) may possess. Unless otherwise mentioned or indicated, thechemical designation of a compound encompasses the mixture of allpossible stereochemically isomeric forms which said compound maypossess. Said mixture may contain all diastereomers and/or enantiomersof the basic molecular structure of said compound. All stereochemicallyisomeric forms of the compounds of formulae (I), (II), (III), (IV), (V),(VI), (VIII), (VIII) or (IX) both in pure form or in admixture with eachother are intended to be embraced within the scope of the presentinvention.

[0201] Some of the compounds of formulae (I), (II), (III), (IV), (V),(VI), (VII), (VIII) or (IX) may also exist in their tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

[0202] Whenever used hereinafter, the term “compounds of formulae(I),(II), (III), (IV), (V), (VI), (VII), (VIII) or (IX)” is meant to includealso the pharmaceutically acceptable acid or base addition salts and allstereoisomeric forms.

[0203] Other farnesyl protein transferase inhibitors which can beemployed in accordance with the present include Arglabin, perrilylalcohol, SCH-66336,2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone (Merck); L778123, BMS 214662, Pfizer compounds A and B describedabove. These compounds can be prepared, for example, by methodsdescribed in the relevant patent specifications identified above whichare incorporated herein by reference.

[0204] Suitable dosages for the compounds Arglabin (WO98/28303),perrilyl alcohol (WO 99/45712), SCH-66336 (U.S. Pat. No. 5,874,442),L778123 (WO 00/01691),2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone (WO94/10138), BMS 214662 (WO 97/30992), Pfizer compounds A and B(WO 00/12499 and WO 00/12498) are given in the aforementioned patentspecifications which are incorporated herein by reference or are knownto or can be readily determined by a person skilled in the art.

[0205] In relation to perrilyl alcohol, the medicament may beadministered 1-4g per day per 150 lb human patient. Preferably, 1-2 gper day per 150 1b human patient. SCH-66336 typically may beadministered in a unit dose of about 0.1 mg to 100 mg, more preferablyfrom about 1 mg to 300 mg according to the particular application.Compounds L778123 and1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinonemay be administered to a human patient in an amount between about 0.1mg/kg of body weight to about 20 mg/kg of body weight per day,preferably between 0.5 mg/kg of bodyweight to about 10 mg/kg of bodyweight per day.

[0206] Pfizer compounds A and B may be administered in dosages rangingfrom about 1.0 mg up to about 500 mg per day, preferably from about 1 toabout 100 mg per day in single or divided (i.e. multiple) doses.Therapeutic compounds will ordinarly be administered in daily dosagesranging from about 0.01 to about 10 mg per kg body weight per day, insingle or divided doses.

[0207] BMS 214662 may be administered in a dosage range of about 0.05 to200 mg/kg/day, preferably less than 100 mg/kg/day in a single dose or in2 to 4 divided doses.

[0208] This invention is especially applicable to the treatment oftumors expressing an activated ras oncogene. Examples of tumors whichmay be inhibited include, but are not limited to, lung cancer (e.g.adenocarcinoma and including non-small cell lung cancer), pancreaticcancers (e.g. pancreatic carcinoma such as, for example exocrinepancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, suchas, for example, colon adenocarcinoma and colon adenoma), hematopoietictumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-celllymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas andrhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas,gliomas, benign tumor of the skin (e.g. keratoacanthomas), breastcarcinoma (e.g. advanced breast cancer), kidney carninoma, ovarycarcinoma, bladder carcinoma and epidermal carcinoma.

[0209] Farnesyl protein transferase inhibitors can be prepared andformulated into pharmaceutical compositions by methods known in the artand in particular according to the methods described in the publishedpatent specifications mentioned herein and incorporated by reference;for the compounds of formulae (I), (II) and (III) suitable examples canbe found in WO-97/21701. Compounds of formulae (IV), (V), and (VI) canbe prepared and formulated using methods described in WO 97/16443,compounds of formulae (VII) and (VIII) according to methods described inWO 98/40383 and WO 98/49157 and compounds of formula (IX) according tomethods described in WO 00/39082 respectively. To prepare theaforementioned pharmaceutical compositions, a therapeutically effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for systemic administration such as oral,percutaneous, or parenteral administration; or topical administrationsuch as via inhalation, a nose spray, eye drops or via a cream, gel,shampoo or the like. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable solutions containing compounds of formula (I) maybe formulated in an oil for prolonged action. Appropriate oils for thispurpose are, for example, peanut oil, sesame oil, cottonseed oil, cornoil, soy bean oil, synthetic glycerol esters of long chain fatty acidsand mixtures of these and other oils. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wettable agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause any significant deleterious effects on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment. As appropriate compositions fortopical application there may be cited all compositions usually employedfor topically administering drugs e.g. creams, gellies, dressings,shampoos, tinctures, pastes, ointments, salves, powders and the like.Application of said compositions may be by aerosol, e.g. with apropellent such as nitrogen, carbon dioxide, a freon, or without apropellent such as a pump spray, drops, lotions, or a semisolid such asa thickened composition which can be applied by a swab. In particular,semisolid compositions such as salves, creams, gellies, ointments andthe like will conveniently be used.

[0210] It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

[0211] The above farnesyl trasferase inhibitor may be used incombination with one or more other anti-cancer agents such as platinumcoordination compounds for example cisplatin or carboplatin, taxanecompounds for example paclitaxel or docetaxel, camptothecin compoundsfor example irinotecan or topotecan, anti-tumor vinca alkaloids forexample vinblastine, vincristine or vinorelbine, anti-tumor nucleosidederivatives for example 5-fluorouracil, gemcitabine or capecitabine,nitrogen mustard or nitrosourea alkylating agents for examplecyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumoranthracycline derivatives for example daunorubicin, doxorubicin,idarubicin or epirubicin; HER2 antibodies for example trastzumab;anti-tumor podophyllotoxin derivatives for example etoposide orteniposide; and antiestrogen agents including estrogen receptorantagonists or selective estrogen receptor modulators preferablytamoxifen, or alternatively toremifene, droloxifene, faslodex andraloxifene, or aromatase inhibitors such as exemestane, anastrozole,letrazole and vorozole.

[0212] The farnesyl transferase inhibitor and the further anti-canceragent may be administered simultaneously (e.g. in separate or unitarycompositions) or sequentially in either order. In the latter case, thetwo compounds will be administered within a period and in an amount andmanner that is sufficient to ensure that an advantageous or synergisticeffect is achieved. It will be appreciated that the preferred method andorder of administration and the respective dosage amounts and regimesfor each component of the combination will depend on the particularfarnesyl transferase inhibitor and further anti-cancer agents beingadministered, their route of administration, the particular tumor beingtreated and the particular host being treated. The optimum method andorder of administration and the dosage amounts and regime can be readilydetermined by those skilled in the art using conventional methods and inview of the information set out herein.

[0213] The FPT inhibitor for use in accordance with the presentinvention may be prepared in a conventional manner, for example, by theprocesses described in the above patent specifications

[0214] The following examples describe the invention in greater detailand are intended to illustrate but not to limit the invention.

EXAMPLE 1

[0215] Materials and Methods

[0216] Cell Culture: CAPAN-2 human pancreatic carcinoma cells werepurchased from the American Type Culture Collection (Rockville, Md.).Cells were maintained in McCoys 5A Medium supplemented with 10% fetalcalf serum and penicillin-streptomycin. NIH 3T3 cells transfected withthe activated T24 H-ras oncogene (T24 cells ) were obtained from,Janssen Research Foundation (For methods see Parada, L. F., Tabin, C.J., Shih, C., and Weinberg, R Human EJ bladder carcinoma oncogene ishomologue of Harvey sarcoma virus ras gene. Nature 297: 474-478, 1982.;Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S., and Barbacid,M. T24 human bladder carcinoma oncogene is an activated form of thenormal human homologue of BALB-and Harvey-MSV transforming genes. Nature298: 343-347, 1982.) T24 cells were maintained as monolayer cultures inDulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% Nu-serumType IV (Collaborative Biomedical Products, Bedford, Mass. and 40 μg/mlG418 (Geneticin®, GIBCO-BRL, Gaithersburg, Md.).

[0217] Animals: Female nu/nu immunodeficient nude mice (42 days old)were purchased from Charles River Laboratories (Wilmington, Mass.). Micewere housed five per cage in microisolator cages placed in laminar flowshelving to maintain sterility. All bedding, food, water and cages wereautoclaved. Animals were handled within the sterile confines of alaminar flow cabinet. The mice were otherwise maintained under standardvivarium conditions. Tumor studies were conducted under a protocolapproved by the Institutional Animal Care and Use Committee.

[0218] Tumor Studies In Nude Mice: Cells growing as monolayers in T150tissue culture flasks were detached by trypsinization with 10 ml of 0.05% trypsin plus 0.53 mM EDTA per flask. Tumor cell suspensions werepooled and trypsin was inactivated by the addition of serum containingmedium (10 ml per 40 ml of trypsin cell suspension). Cells werecollected by centrifugation and resuspended in Hank's Balanced SaltSolution (HBSS) warmed to 37° C. A 1.0 ml portion of cell suspension wasadded to 20 ml of diluent and counted on a Coulter particle counter. Thecell suspensions were recentrifuged and resuspended at a concentrationof 1×10⁶ cell per 0.10 ml of HBSS. Mice were inoculated with a singlesubcutaneous injection of 0.10 ml of tumor cell suspension in theinguinal region. Mice were housed five per cage with 15 mice assigned toeach treatment group. Body weight and tumor size as determined bycaliper measurements were measured weekly. The caliper measurements oflength and width were multiplied to obtain tumor areas. At the end ofstudy, mice were sacrificed by CO₂ asphyxiation.

[0219] Three days after tumor inoculation, the five day treatment with(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(compound 1) was initiated. Compound 1 was administered once daily byoral gavage in a 20% beta-cyclodextrin vehicle as a volume of 0.10 ml ofsolution per 10 gm body weight. Control groups received the same dosagevolume of the 20% beta-cyclodextrin vehicle.

[0220] Compounds. Compound 1 was prepared for oral administration bydissolving the compound first as a 2× concentrated stock in 40%hydroxypropyl beta cyclodextrin (lot no. 051-071/1) in 0.1 N HCI.Compound 1 was dissolved by stirring vigorously approximately 30 minutesfollowed by sonication for 10 min. The compound 1 solutions were broughtto a final concentration by diluting 1:1 with 0.1 N HCI. The final drugsolutions were sterile filtered immediately and transferred to steriletubes. Solutions were stored refrigerated and protected form lightduring the course of the study and sterility was maintained by openingsolutions under sterile laminar flow conditions.

Results and Discussion

[0221] Presented in FIG. 1 are the results of studying intermittentdosing of compound 1. Compound 1 was administered once daily for fivedays every three weeks to nude mice bearing the T24 H-ras tumors.Vehicle treated animals presented with aggressively growing tumors 14days after inoculation. This group was sacrificed on day 17 since theirtumors exceeded the ethical guideline of a tumor burden no greater than10% animal. body weight. Mice treated with 200 mg/kg compound I for fivedays (days 3-8 after tumor inoculation) presented with small tumors onday 17. Left untreated, the tumors returned to the rapid control growthrates by day 24. Animals were sacrificed on day 28 again according toethical guidelines. A separate group of 15 mice received an additional5-day treatment with 200 mg/kg compound 1. Tumor growth was againarrested but not as dramatically as in the initial treatment.

[0222] An identical dosing schedule was investigated in CAPAN-2 humanpancreatic tumors in nude mice. Administration of compound 1 for fivedays at a dose of 200 mg/kg significantly reduced the growth of CAPAN-2tumors out to day 24 (FIG. 2). Thereafter, tumors receiving no furthertreatment returned to the growth rate observed for vehicle treatedcontrols. Again, a separate group of 15 animals received an additionalfive-day treatment with compound 1 on days 21 to 25. Only, a transientgrowth arrest, which was significant on day 28 of study, was produced.Although the response of the CAPAN-2 tumors was not as dramatic as theT24 tumors, the present results are remarkable when compared to previousstudies. In our original evaluation of CAPAN-2 tumors with compound 1administered twice daily on a continuous schedule for 18 days, doses of50 mg/kg (100 mg/kg total daily dose) and 100 mg/kg (200 mg/kg) dailydose produced significant reductions of tumor growth. The five-daydosing schedule was a marked reduction in drug exposure from thisprevious study. Yet, an antitumor effect was still maintained

[0223] The dose dependency of the abbreviated five-day dosing schedulewas explored in T24 tumors at compound 1 doses of 50, 100 and 200 mg/kg.The duration of response was dose-related with the 200 mg dose againproducing sustained effects out to day 17 of study (FIG. 3). The tumorsuppressive effects of the lower doses waned by day 14. Significant,dose-related reductions of tumor growth measured as final tumor area(FIG. 4) and final tumor weights (FIG. 5) were still observed on day 17of study for all compound 1 treatment groups. The highest tested dose of200 mg/kg was substantially more effective than the lower does with a90% reduction of final tumor weights observed.

[0224] Finally, to address the minimum duration of FPT inhibitorexposure required to elicit an antitumor effect, animals were treatedwith a single administration of compound 1. As shown in FIG. 6, a single200 mg/kg or 400 mg/kg dose of compound 1 given three days after tumorinoculation produced a sustained inhibition of tumor growth lasting outto 15 days.

[0225] The present studies demonstrate that abbreviated five-dayexposures to compound 1 can produce antitumor effects which persist foran additional two weeks or greater beyond the treatment.

[0226]FIG. 1. Inhibition of the growth of T24 H-ras transformed NIH3T3cell tumors by compound 1 administered as five-day intermittenttreatments. Nude mice were inoculated with 1×10⁶ T24 cellssubcutaneously on day 0. After three days, oral dosing withbeta-cyclodextrin vehicle (100 μl per 10 gm body weight) or compound 1(200 mg/kg) was initiated. One treatment group was treated for anadditional five days starting on day 21. Tumor size is expressed astumor area (length×width). Values are means (±SEM) for N=14-15 animalsper treatment group. For figure clarity, values significantly (p <0.05by ANOVA) different from the vehicle treatment group are indicated (*)for day 21 only. Significant effects for the second treatment cycle withcompound 1 are indicated for day 28 (**).

[0227]FIG. 2. Inhibition of tumor growth in CAPAN-2 human pancreatictumors produced by intermittent five day treatments with compound 1 (200mg/kg, p.o.) Nude mice were inoculated with 1×10⁶ CAPAN-2 cellssubcutaneously. After three days, oral dosing with beta-cyclodextrinvehicle (100 μl per 10 gm body weight) or compound 1 (200 mg/kg) wasinitiated. One treatment group was treated for an additional five daysstarting on day 21. Tumor size is expressed as tumor area(length×width). Values are means (±SEM) for N=14-15 animals pertreatment group. For figure clarity, values significantly (p<0.05 byANOVA) different from the vehicle treatment group are indicated (*) forday 24. Significant effects for the second treatment cycle with compound1 are indicated for day 28 (**).

[0228]FIG. 3. Time course for inhibition of the growth of T24 U-rastransformed NIH3T3 cell tumors by compound 1 administered as a singlefive-day treatment. Nude mice were inoculated with 1×10⁶ T24 cellssubcutaneously on day 0. After three days, daily oral dosing withbeta-cyclodextrin vehicle (100 μl per 10 gm body weight) or theindicated doses of compound 1 was initiated by oral gavage. Tumor sizeis expressed as tumor area (length×width). Values are means for N=14-15animals per treatment group. Statistical analyses for tumor measurementscollected at termination of study at day 17 are presented in FIGS. 4 and5.

[0229]FIG. 4. Inhibition of the growth of T24 H-ras transformed NIH3T3cell tumors by compound 1 administered as a single five-day treatment.Nude mice were inoculated with 1×10⁶ T24 cells subcutaneously on day 0.After three days, oral dosing with beta-cyclodextrin vehicle (100 μl per10 gm body weight) or the indicated doses of compound 1 was initiated byoral gavage. Tumor size is expressed as tumor area (length x width).Values are means (±SEM) for N=14-15 animals per treatment group. Valueswith the same letter are not significantly different (p<0.05 by ANOVA).The per cent reduction in tumor size is presented over each histogrambar.

[0230]FIG. 5. Inhibition of the growth of T24 H-ras transformed NIH3T3cell tumors by compound 1 administered as a single five-day treatment.Nude mice were inoculated with 1×10⁶ T24 cells subcutaneously on day 0.After three days, oral dosing with beta-cyclodextrin vehicle (100 μl per10 gm body weight) or the indicated doses of compound 1 was initiated byoral gavage. Tumor size is expressed as post mortem tumor weight (g).Values are means (±SEM) for N=14-15 animals per treatment group. Valueswith the same letter are not significantly different (p<0.05 by ANOVA).The per cent reduction in tumor weight is indicated over each histogrambar.

[0231]FIG. 6. Time course for inhibition of the growth of T24 H-rastransformed NIH3T3 cell tumors by compound 1 administered as asingle-treatment. Nude mice were inoculated with 1×10⁶ T24 cellssubcutaneously on day 0. After three days, daily oral dosing withbeta-cyclodextrin vehicle (100 μl per 10 gm body weight) or theindicated doses of compound 1 was initiated by oral gavage. Tumor sizeis expressed as tumor area (length x width). Values are means forN=14-15 animals per treatment group.

What is claimed is:
 1. A method for the treatment of cancer in mammalswhich comprises administering a farnesyl protein transferase inhibitoronce daily over a period of one to five days.
 2. The method of claim 1wherein the farnesyl protein transferase inhibitor is administered at adose of 50-1200 mg/kg body weight.
 3. The method of claim 1 wherein thefarnesyl protein transferase inhibitor is administered at a dose of50-400 mg/kg body weight.
 4. The method of claim 1 wherein the farnesylprotein transferase inhibitor is administered at a dose of 50-200 mg/kgbody weight.
 5. The method of claim 1 wherein the farnesyl proteintransferase inhibitor is administered for one day.
 6. The method ofclaim 1 wherein the farnesyl protein transferase inhibitor isadministered for five days.
 7. The method of claim 1 wherein thefarnesyl protein transferase inhibitor is selected from compounds offormulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX)below:

a stereoisomeric form thereof, a pharmaceutically acceptable acid orbase addition salt thereof, wherein the dotted line represents anoptional bond; X is oxygen or sulfur; R¹ is hydrogen, C₁₋₂alkyl, Ar¹,Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or—Alk¹—S(O)₂—R⁹, wherein Alk¹ is C₁₋₆alkanediyl, R⁹ is hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylaminosubstituted with C₁₋₆alkyloxycarbonyl; R², R³ and R¹⁶ each independentlyare hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or when on adjacentpositions R² and R³ taken together may form a bivalent radical offormula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2)—O—CH═CH—  (a-3)—O—CH₂—CH₂—  (a-4)—O—CH₂—CH₂—CH₂—  (a-S)or —CH═CH—CH═CH—  (a-6) R⁴ and R⁵ each independently are hydrogen, halo,Ar¹, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylthio, amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl; R⁶ and R⁷ eachindependently are hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy,Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, or when onadjacent positions R⁶ and R⁷ taken together may form a bivalent radicalof formula —O—CH₂—O—  c-1) or —CH═CH—CH═CH—  (c-2) R⁸ is hydrogen,C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula —O—R¹⁰  (b-1)—S—R¹⁰  (b-2)—N—R¹¹R¹²  (b-3) whereinR¹⁰is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, a radical or formula —Alk²—OR¹³ or-Alk²-NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹or Ar²C₁₋₆alkyl; R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy-carbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, anatural amino acid, Ar¹carbonyl, Ar²C₁₋₆alkylcarbonyl,aminocarbonylcarbonyl, C₁₋₆alkyloxy-C₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical of formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵; wherein Alk² is C₁₋₆alkanediyl; R¹³ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr²C₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁵ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁷ ishydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹; R¹⁸ ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo; R¹⁹ is hydrogen or C₁₋₆alkyl;Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and Ar² is phenyl or phenyl substituted withC₁₋₆alkyl, hydroxy, amino, C₁₋₆alkyloxy or halo;

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond; X is oxygen or sulfur; R¹ is hydrogen,C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)-aminoC₁₋₆alkyl, aminoC₁₋₆alkyl, or a radical of formula—Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or —Alk¹—S(O)₂—R⁹, wherein Alk¹ isC₁₋₆alkanediyl, R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino,C₁₋₈alkylamino or C₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;R² and R³ each independently are hydrogen, hydroxy, halo, cyano,C¹⁻⁶alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,amino-C₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar²C₁₋₆alkyl, Ar²oxy, Ar²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl; orwhen on adjacent positions R² and R³ taken together may form a bivalentradical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2)—O—CH═CH—  (a-3)—O—CH₂—CH₂—  (a-4)—O—CH₂—CH₂—CH₂—  (a-5)or —CH═CH—CH═CH—  (a-6) R⁴ and R⁵ each independently are hydrogen, Ar¹,C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R⁶ and R⁷ each independently are hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy or Ar²oxy; R⁸ is hydrogen,C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyl-carbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, hydroxy-carbonylC₁₋₆alkyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, Ar¹,Ar²C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl; R¹⁰ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy or halo; R¹¹ is hydrogen or C₁₋₆alkyl; Ar¹ isphenyl or phenyl substituted with C₁₋₆alkyl,hydroxy,amino,C₁₋₆alkyloxyor halo; Ar² is phenyl or phenyl substituted withC₁₋₆alkyl,hydroxy,amino, C₁₋₆alkyloxy or halo.

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond; X is oxygen or sulfur; —A— is a bivalentradical of formula —CH═CH— (a-1), —CH₂—S— (a-6), —CH₂—CH₂— (a-2),—CH₂—CH₂—S— (a-7), —CH₂—CH₂—CH₂— (a-3), —CH═N— (a-8), —CH₂—O— (a-4),—N═N— (a-9), or —CH₂—CH₂—O— (a-5), —CO—NH— (a-10);

wherein optionally one hydrogen atom may be replaced by C₁₋₄alkyl orAr¹; R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar²,Ar²-C₁₋₆alkyl, Ar²-oxy, Ar²-C₁₋₆alkyloxy; or when on adjacent positionsR¹ and R² taken together may form a bivalent radical of formula—O—CH₂—O—  (b-1)—O—CH₂—CH₂—O—  (b-2)—O—CH═CH—  (b-3)—O—CH₂—CH₂—  (b-4)—O—CH₂—CH₂—CH₂—  (b-5)or —CH═CH—CH═CH—  (b-6) R³ and R⁴ each independently are hydrogen, halo,cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, Ar³-oxy, C₁₋₆alkylthio,di(C₁₋₆alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacentpositions R³ and R⁴ taken together may form a bivalent radical offormula —O—CH₂—O—  (c-1)—O—CH₂—CH₂—O—  (c-2) or —CH═CH—CH═CH—  (c-3) R⁵is a radical of formula

wherein R¹³ is hydrogen, halo, Ar⁴, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxy-C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxy-carbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl; R¹⁴is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;R⁶ is hydrogen, hydroxy, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar⁵,Ar⁵-C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula—O—R⁷  (e-1)—S—R⁷  (e-2)—N—R⁸R⁹  (e-3) wherein R⁷ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar⁶, Ar⁶-C₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula —Alk—OR¹⁰ or—Alk—NR ¹¹R¹²; R⁸ is hydrogen, C₁₋₆alkyl, Ar⁷ or Ar⁷-C₁₋₆alkyl; R⁹ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar⁸, Ar⁸-C₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,Ar⁸-carbonyl, Ar⁸-C₁₋₆alkylcarbonyl, aminocarbonyl-carbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula —Alk—OR¹⁰ or—Alk—NR¹¹R¹²; wherein Alk is C₁₋₆alkanediyl; R¹⁰ is hydrogen, C₁₋₆alkyl,C₁₋₆alkylcarbonyl, hydroxy-C₁₋₆alkyl, Ar⁹ or Ar⁹-C₁₋₆alkyl; R¹¹ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹⁰ or Ar¹⁰-C₁₋₆alkyl; R¹² ishydrogen, C₁₋₆alkyl, Ar¹¹ or Ar¹¹-C₁₋₆alkyl; and Ar¹ to Ar¹¹ are eachindependently selected from phenyl; or phenyl substituted with halo,C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl.

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein the dotted linerepresents an optional bond; X is oxygen or sulfur; R¹ and R² eachindependently are hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl,trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar¹C₁₋₆alkyl, Ar¹oxy or Ar¹C₁₋₆alkyloxy; R³ and R⁴ each independentlyare hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, Ar¹oxy,C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, trihalomethyl or trihalomethoxy; R⁵is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar¹,Ar¹C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula—O—R¹⁰  (a-1)—S—R¹⁰  (a-2)—N—R¹¹R¹²  (a-3) wherein R¹⁰ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹, Ar¹C₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula —Alk—OR¹³ or—Alk—NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl; R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar¹C₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,Ar¹carbonyl, Ar¹C₁₋₆alkylcarbonyl, aminocarbonyl-carbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula —Alk—OR¹³ or—Alk—NR¹⁴R¹⁵; wherein Alk is C₁₋₆alkanediyl; R¹³ is hydrogen, C₁₋₆alkyl,C₁₋₆alkylcarbonyl, hydroxy-C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl; R¹⁴ ishydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl,C₁₋₆alkylcarbonyl, Ar¹ or Ar¹C₁₋₆alkyl; R⁶ is a radical of formula

wherein R¹⁶is hydrogen, halo, Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxy-C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R¹⁷is hydrogen, C₁₋₆alkyl ordi(C₁₋₄alkyl)aminosulfonyl; R⁷ is hydrogen or C₁₋₆alkyl provided thatthe dotted line does not represent a bond; R⁸ is hydrogen, C₁₋₆alkyl orAr²CH₂ or Het¹CH₂; R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo; orR⁸ and R⁹ taken together to form a bivalent radical of formula—CH═CH—  (c-1)—CH₂—CH₂—  (c-2)—CH₂—CH₂—CH₂  (c-3)—CH₂—O—  (c-4) or—CH₂—CH₂—O—  (c-5) Ar¹ is phenyl; or phenyl substituted with 1 or 2substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy or trifluoromethyl; Ar² is phenyl; or phenyl substitutedwith 1 or 2 substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl; and Het¹ is pyridinyl;pyridinyl substituted with 1 or 2 substituents each independentlyselected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl and

or the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein ═X¹—X²—X³— is atrivalent radical of formula ═N—CR⁶═CR⁷— (x-1), ═CR⁶—CR⁷═CR⁸— (x-6),═N—N═CR⁶— (x-2), ═CR⁶—N═CR⁷— (x-7), ═N—NH—C(═O)— (x-3), ═CR⁶—NH—C(═O)—(x-8), or ═N—N═N— (x-4), ═CR⁶—N═N— (x-9); ═N—CR⁶═N— (x-5),

wherein each R⁶, R⁷ and R⁵ are independently hydrogen, C₁₋₄alkyl,hydroxy, C₁₋₄alkyloxy, aryloxy, C₁₋₄alkyloxycarbonyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl, cyano,amino, thio, C₁₋₄alkylthio, arylthio or aryl; >y¹—y²— is a trivalentradical of formula >CH—CHR⁹—  (y-1)>C═N—  (y-2)>CH—NR⁹—  (y-3) or>C═CR⁹—  (y-4) wherein each R⁹ independently is hydrogen, halo,halocarbonyl, aminocarbonyl, hydroxyC₁₋₄alkyl, cyano, carboxyl,C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,mono- or di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl, aryl;r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0,1,2 or 3; eachR¹ and R² are independently hydroxy, halo, cyano, C₁₋₆alkyl,trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)amino,mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, aryloxy orarylC₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminocarbonyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl; or two R¹ or R² substituents adjacent toone another on the phenyl ring may independently form together abivalent radical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2)—O═CH═CH—  (a-3)—O—CH₂—CH₂—  (a-4)—O—CH₂—CH₂—CH₂—  (a-5)or —CH═CH—CH═CH—  (a-6) R³ is hydrogen, halo, C₁₋₆alkyl, cyano,haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,hydroxycarbonyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, aryl, arylC₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)amino C₁₋₆alkyl; or a radical of formula—O—R¹⁰  (b-1)—S—R¹⁰  (b-2)—NR¹¹R¹²  (b-3) wherein R¹⁰ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl, arylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula —Alk—OR¹³ or—Alk—NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl; R¹² ishydrogen, C₁₋₆alkyl, aryl, hydroxy, amino, C₁₋₆alkyloxy,C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl, C₁₋₆alkylcarbonylamino, mono-or di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonyl, aminocarbonyl, arylcarbonyl,haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonylwherein the alkyl moiety may optionally be substituted by one or moresubstituents independently selected from aryl or C₁₋₃alkyloxycarbonyl,aminocarbonylcarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, ora radical or formula —Alk—OR¹³ or —Alk—NR¹⁴R¹⁵; wherein Alk isC₁₋₆alkanediyl; R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl,aryl or arylC₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,aryl or arylC₁₋₆alkyl; R⁴ is a radical of formula

wherein R¹⁶ is hydrogen, halo, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino, mono- ordi(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R¹⁶ may also be bound to one of the nitrogenatoms in the imidazole ring of formula (c-1) or (c-2), in which case themeaning of R¹⁶ when bound to the nitrogen is limited to hydrogen, aryl,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;R¹⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyl,trifluoromethyl or di(C₁₋₄alkyl)aminosulfonyl; R⁵ is C₁₋₆alkyl ,C₁₋₆alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substitutedwith 1 or more substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl.
 8. The method of claim 7wherein said farnesyl protein transferase inhibitor is a compound offormula (I) wherein X is oxygen and the dotted line represents a bond.9. The method of claim 7 or claim 8 wherein said farnesyl proteintransferase inhibitor is a compound of formula (I) wherein R¹ ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy-C₁₋₆alkyl or mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, R³ is hydrogen and R² is halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy or hydroxyC₁₋₆alkyloxy. 10.The method of any of claims 7 to 9 wherein said farnesyl proteintransferase inhibitor is a compound of formula (I) wherein R⁸ ishydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radical of formula—NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, or aradical of formula —Alk²—OR¹³ wherein R¹³ is hydrogen or C₁₋₆alkyl. 11.The method of claim 7 wherein the farnesyl protein transferase inhibitoris4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)-methyl]-1-methyl-2(1H)-quinolinone,6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone;6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride.monohydrate;6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone,and6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone;a stereoisomeric form thereof or a pharmaceutically acceptable acid orbase addition salts thereof.
 12. The method of claim 7 wherein thefarnesyl protein transferase inhibitor is(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.
 13. Themethod of claim 7 wherein the farnesyl protein transferase inhibitor isa compound of formula (IX) wherein ═X¹—X²—X³ is a trivalent radical offormula (x-2) or (x-3) or (x-4), >Y1-Y2 is a trivalent radical offormula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R¹ is halo,preferably chloro, and most preferably 3-chloro or R¹ is C₁₋₄alkyl,preferably 3-methyl, R² is halo, preferably chloro, and most preferably4-chloro, R³ is a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-2), R⁶ is C₁₋₄alkyl, R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogenand R¹² is hydrogen or hydroxy.
 14. The method of claim 7 wherein thefarnesyl protein transferase inhibitor is5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamineor a pharmaceutically acceptable acid addition salt thereof.
 15. Adosage regimen for the treatment of mammalian cancers which comprisesadministering 50-1200 mg/kg body weight of a farnesyl proteintransferase inhibitor once daily over a period of one to five daysfollowed by two weeks without treatment.
 16. The dosage regimen of claim15 wherein the farnesyl protein transferase inhibitor is administered ata dose of 50-1200 mg/kg body weight.
 17. The regimen of claim 15 whereinthe farnesyl protein transferase inhibitor is administered at a dose of50-400 mg/kg body weight.
 18. The dosage regimen of claim 15 wherein thefarnesyl protein transferase inhibitor is administered at a dose of50-200 mg/kg body weight.
 19. The dosage regimen of claim 15 wherein thefarnesyl protein transferase inhibitor is administered for one day. 20.The dosage regimen of claim 15 wherein the farnesyl protein transferaseinhibitor is administered for five days.
 21. The dosage regimen of claim15 wherein the farnesyl protein transferase inhibitor is selected fromcompounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII)and (IX) (as defined in claim 7).
 22. The dosage regimen of claim 21wherein said farnesyl protein transferase inhibitor is a compound offormula (I) wherein X is oxygen and the dotted line represents a bond.23. The dosage regimen of claim 21 or claim 22 wherein said farnesylprotein transferase inhibitor is a compound of formula (1) wherein R¹ ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl or mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, R³ is hydrogen and R² is halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy or hydroxyC₁₋₆alkyloxy. 24.The dosage regimen of claims 21 to 23 wherein said farnesyl proteintransferase inhibitor is a compound of formula (I) wherein R⁸ ishydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radical of formula—NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, or aradical of formula —Alk²—OR¹³ wherein R¹³ is hydrogen or C₁₋₆alkyl. 25.The dosage regimen of claim 21 wherein said farnesyl protein transferaseinhibitor is4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)-methyl]-1-methyl-2(1H)-quinolinone,6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone;6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride.monohydrate;6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone,and6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone;a stereoisomeric form thereof or a pharmaceutically acceptable acid orbase addition salts thereof.
 26. The dosage regimen of claim 21 whereinthe farnesyl protein transferase inhibitor is(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.
 27. Thedosage regimen of claim 21 wherein the arnesyl protein transferaseinhibitor is a compound of formula (IX) wherein ═X¹—X²—X³ is a trivalentradical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a trivalent radicalof formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R¹ is halo,preferably chloro, and most preferably 3-chloro or R¹ is C₁₋₄alkyl,preferably 3-methyl, R² is halo, preferably chloro, and most preferably4-chloro, R³ is a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-2), R⁶ is C₁₋₄alkyl, R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogenand R¹² is hydrogen or hydroxy.
 28. The dosage regimen of claim 21wherein the farnesyl protein transferase inhibitor is5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamineor a pharmaceutically acceptable acid addition salt thereof.
 29. Use ofa farnesyl protein transferase inhibitor in the manufacture of amedicament for the treatment of cancer in mammals in which the farnesylprotein transferase inhibitor is administered once daily over a periodof one to five days.